Diseases, disorders, and injuries of the central nervous system are associated with loss and/or dysfunction of neurons and/or glia. These diseases, disorders, and injuries range from simple monogenetic diseases to complex acquired disorders and trauma. These diseases, disorders, and injuries include, but are not limited to, stroke, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, brain trauma, spinal cord injury, myelin disorders, immune and autoimmune disorders, metabolic and storage diseases including all of the leukodystrophies and lysosomal storage diseases, and other degenerative, oncological, metabolic, or senescence-related diseases and disorders of the central nervous system (CNS). These neurodegenerative diseases, as well as the neurological damage associated with these conditions, are very difficult to treat and were thought to be irreversible because of the inability of neurons and other cells of the nervous system to grow in the adult body.
However, the recent advent of stem cell-based therapy for tissue repair and regeneration provides promising treatments for a number of neurodegenerative pathologies and other neurological disorders. Accumulating evidence suggests that delivery of therapeutic stem cells to the brain of a human can have a potential beneficial effect in treating many diseases, disorders, and injuries with central nervous system involvement since stem cells are capable of self-renewal and differentiation to generate a variety of mature neural cell lineages. These diseases, disorders, and injuries include, but are not limited to, stroke, brain trauma and neurodegenerative conditions such as Alzheimer's, Parkinson's and Huntington's diseases.
However, there are many hurdles preventing therapeutic agents as well as therapeutic stem cells, from reaching a diseased brain. For instance, systemic delivery of therapeutic agents to the CNS is ineffective for most small molecules and nearly all large molecules. The main impediment in most cases is the blood-brain barrier (BBB). Necessary for protection against bacterial infections, the BBB prevents most foreign substances, including potential therapeutic agents and stem cells, from entering the brain from capillaries.
Early conventional approaches or strategies to bypassing (circumventing) the blood brain barrier using IV infusion via intrathecal or intracranial routes have not yielded unanimous or encouraging reproducible results. In addition, each of these approaches included limitations, such as the inherent risks associated with an invasive surgical procedure, and potentially undesirable side effects associated with the systemic administration of therapeutic agents. Similarly, the blood brain barrier has presented a significant obstacle to efficient and effective delivery of stem cells to the brain using noninvasive techniques such as suspension solutions or ointment delivered by intranasal sprays or direct intranasal application of drops or ointment to nasal tissue, e.g., by swab or pledget, because of the unpredictable effect of cilia activity, moisture and humidity and air flow currents that occur normally in the nose. Moreover, these delivery approaches have proven to be suboptimal in reaching target sites beyond the nasal valve, e.g., damaged regions within the brain and/or CNS, due to their inability to reach the olfactory region of the brain as well as their very limited ability to deposit therapeutic stems cells within the damaged regions of the brain and/or CNS. As a result of these factors, the dose and potential absorption of the therapeutic stem cells is presently unpredictable.
Other prior approaches to bypassing the BBB have attempted intranasal injection of stem cell solutions using a nasal speculum and different light sources by inserting a needle into the periosteum or subperichondrial regions of non-specific areas of the nose. However, these approaches have proven to be unsatisfactory because of the lack of non-specificity of the region chosen for injection and the avascular nature of the location where the cells are deposited. In addition, the use of routine vasoconstrictors during surgery, for example, oxymetazoline, phenylephrine or cocaine, has further hampered the success of this approach. Nonetheless, accumulating evidence suggests that IN delivery of stem cells may be a viable approach for treatment of CNS pathology since complications associated with intravascular delivery, such as obstruction of the BBB, pulmonary embolism and infarctions, could also be avoided using the approach.
Therefore, since none of the methods discussed above has resulted in a combination of high efficiency and low side effects delivery of potential therapeutics (including stem cells) to the brain and/or CNS, there still exists a need for a better method to optimize or enhance delivery of therapeutics, particularly therapeutic stem cells, to the tissues and cells of the brain and/or CNS.